Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
J Med Chem. 2024 Apr 25;67(8):6549-6569. doi: 10.1021/acs.jmedchem.3c02483. Epub 2024 Apr 11.
Fibroblast growth factor receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that noncanonical covalent "warheads" based on nucleophilic aromatic substitution (SAr) chemistry can be employed in a rational manner to generate highly potent and (isoform-)selective FGFR4 inhibitors with a low intrinsic reactivity. Key compounds showed low to subnanomolar potency, efficient covalent inactivation kinetics, and excellent selectivity against the other FGFRs, the kinases with an equivalent cysteine, and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability, highlighting the potential of SAr-based approaches in covalent inhibitor design.
成纤维细胞生长因子受体 4（FGFR4）被认为是多种癌症类型的驱动因素，尤其是在肝细胞癌中。实现 FGFR4 高效力和同工型选择性的一种方法是通过共价靶向其激酶结构域铰链区域中罕见的半胱氨酸（C552），该半胱氨酸不存在于其他 FGFR 家族成员（FGFR1-3）中。通常，这种半胱氨酸是通过经典丙烯酰胺亲电试剂来解决的。我们证明，基于亲核芳香取代（SAr）化学的非典型共价“弹头”可以以合理的方式用于生成具有低固有反应性的高效力和（同工型）选择性 FGFR4 抑制剂。关键化合物表现出低至亚纳摩尔的效力、有效的共价失活动力学以及对其他 FGFR、具有等效半胱氨酸的激酶和激酶组的代表性亚组的出色选择性。此外，这些化合物在细胞测定中达到纳摩尔效力，并表现出良好的微粒体稳定性，突出了基于 SAr 的方法在共价抑制剂设计中的潜力。
